One of the primary distinguishing characteristics of cancer is the abnormally rapid division and proliferation of malignant cells. This is exploited in many current forms of chemotherapy, which have a greater effect on rapidly dividing cells than quiescent cells. Thus, normal, slowly dividing cells are less affected than malignant cells. Unfortunately, several cell types normally divide quickly, including the cells associated with hair follicles, intestinal lining, and hematopoiesis. The depression of hematopoiesis following chemotherapy is the most serious side effect, and in many cases leaves the patient susceptible to opportunistic infection due to the relative lack of lymphocytes, macrophages and granulocytes.
There are several known growth factors which are believed necessary for the induction and terminal differentiation of myeloid cells. Granulocyte-macrophage colony stimulating factor (GM-CSF) stimulates the formation of blast cells capable of differentiating into granulocytes (neutrophils and eosinophils) and macrophage/monocytes. Granulocyte colony stimulating factor (G-CSF) stimulates the production of granulocytes (predominantly neutrophils) from granulocyte/macrophage precursor cells. Macrophage colony stimulating factor (M-CSF) stimulates the production of monocyte/macrophages from granulocyte/macrophage precursor cells. Although it might seem a natural solution to administer GM-CSF, G-CSF, and/or M-CSF to patients undergoing chemotherapy, these cytokines may be effective only at toxic doses.
Seyedin, U.S. Pat. No. 4,774,322 filed Dec. 10, 1987, described two bovine bone-derived cartilage inducing factors (CIFs), designated CIF-A and CIF-B. Both have molecular weights of approximately 26,000 daltons by SDS-PAGE and are dimers. They each exhibit in vitro chondrogenic activity by themselves, as measured by cartilage specific proteoglycan (PG) production in an agarose gel culture model using fetal rat mesenchymal cells. Neither, however, is chondrogenically active in vivo by itself. Amino acid sequencing of the CIF-A showed that it has a partial (30 amino acids) N-terminal sequence identical to that reported for a human placenta-derived polypeptide called beta-type transforming growth factor (TGF-.beta.). The partial N-terminal sequence of CIF-B is different from that of TGF-.beta.. Both CIFs exhibit activity in the TGF-.beta. assay (ability to induce anchorage-independent growth of normal rat kidney cell colonies in soft agar). CIF-A/TGF-.beta. is now known by the name TGF-.beta.1, while CIF-B is now generally referred to as TGF-.beta.2.
TGF-.beta., when combined with EGF or TGF-alpha, (1) promotes cell proliferation in the soft agar culture assay and (2) promotes cell proliferation and protein deposition in a rat soft tissue wound healing model. The applications characterize the TGF-.beta.s as being dimers having a molecular weight of approximately 26,000 daltons (26 kDa) by SDS-PAGE. TGF-.beta. exhibits a wide variety of activities, which appear to depend in large part to the cell type which is exposed. For example, TGF-.beta. stimulates growth of normal fibroblasts in the presence of EGF or TGF-.alpha., but inhibits the growth of some tumor cells: A. B. Roberts et al, Proc Nat Acad Sci USA (1985) 82:119-23. Bentz et al, U.S. Pat. No. 4,806,523, disclosed the use of TGF-.beta. (also known as CIF-A and CIF-B) to inhibit inflammation, and demonstrated that TGF-.beta. inhibited T-cell proliferation and antibody production. S. Tsunawaki et al, Nature (1988) 334:260-62 found that macrophages incubated with TGF-.beta.1 or TGF-.beta.2 were reversibly deactivated. H. Goey et al, J Immunol (1989) 143: 877-80 reported that administration of TGF-.beta.1 directly to femoral bone marrow in mice in vivo reversibly suppressed the proliferation of pluripotential progenitor cells.